Abused drugs produce long-lasting changes in behaviors via biochemical mechanisms that are largely unknown. Drug-altered changes in expression of specific genes in the brain can provide a major window on possible biochemical substrates for ddiction. To further explore this area, we are now increasingly focused on array hybridization techniques that has allow identification of dozens of distinct cDNAs that correspond to candidate drug- regulated genes expressed in brain. During this year, we have enhanced characterization of candidate genes whose expression is regulated by amphetamine, cocaine and morphine. We can compare these data to results from knockout mice that lack single- or multiple-genes for receptors and transporters. Using microarrays, we have been able to detect reproducible positive hybridization signals from ca 38% of the genes sampled oligonucleotide DNA microarrays, and to identify the ca 1-2% that are reproducibly regulated more than 2-fold by knockouts or drugs. We have extended characterization of these genes.